CN1872337A - Nasal cavity taking preparation of hirudin, and application - Google Patents
Nasal cavity taking preparation of hirudin, and application Download PDFInfo
- Publication number
- CN1872337A CN1872337A CN 200510073407 CN200510073407A CN1872337A CN 1872337 A CN1872337 A CN 1872337A CN 200510073407 CN200510073407 CN 200510073407 CN 200510073407 A CN200510073407 A CN 200510073407A CN 1872337 A CN1872337 A CN 1872337A
- Authority
- CN
- China
- Prior art keywords
- hirudin
- preparation
- rhv2
- chitosan
- normal saline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
An anti-coagulation and anti-thrombosis polypeptide medicine in the form of drops, aerosol, gel or ointment for preventing and/or treating thrombotic diseases by applying it to nasal cavity is prepared from hirudin, absorption promoter, antiseptic, pH regulator, and water or physiologic saline through dissolving antiseptic in water or physiologic saline, sequentially adding sbsorption promoter and hirudin, stirring, adding rest of water or physiologic saline, and using acetic acid to regulate pH=4-6.
Description
Technical field
The present invention relates to a kind of administration new way of anticoagulant thromboembolism preventing polypeptide drugs-hirudin, be specifically related to hirudin and pass through preparation of nasal mucosa administration and uses thereof.
Background technology
Current cardiovascular disease has become the No.1 formidable enemy of harm humans health, and wherein thrombotic disease is serious harm human life's a disease, and people are being devoted to seek and develop the active drug of treatment thrombotic disease always for many years.So far, existing urokinase, streptokinase, thrombolytic drugs such as tissue-type plasminogen activator and prourokinase.Meanwhile people are also seeking the thromboembolism preventing medicine of better effects if always.Hirudin is exactly a kind of thromboembolism preventing medicine (Doutremepuich C., Deharo E., Guyot, M., etal.Thrombos.Res.54:435-445,1989.) of exploitation recently.Hirudo is exactly the good medicine of anti-bolt anticoagulant removing blood stasis since ancient times, and head is stated from Shennong's Herbal, and the back is all recorded in Compendium of Material Medica and monographs such as " Chinese animal drugs ".Just found hirudin as far back as 1884, but after nineteen fifty, just be separated to the hirudin of biologically active from the salivary gland of Hementaria officianalis, pharmacology for hirudin, comprise anticoagulation, influence to platelet, various cells, antithrombotic effect and kinetics, toxicity etc. have all been carried out comprehensive, deep research.Its medical value is generally paid attention to.Hirudin is a kind of Acid polypeptide of the salivary gland secretion of Hirudo, form by 65 or 66 aminoacid, molecular weight is about 7000Da, the strongest special inhibitor of thrombin that is up to now to be found, it is anticoagulation efficiently, the congestion phenomenon that antithrombotic forms and stops reactions such as further activated clotting factor of thrombin and platelet aggregation to cause, multiple thrombotic disease had good curative effect (Walenga J.M., Pifarre R.andFareed J.Drugs of the Future.15 (3): 267-280,1990., Markwardt F., Fink G., Kaiser B., et al.Pharmazie.43:202-207,1988.).Because natural hirudin extracts the preparation difficulty, cost is high, and its research and application are restricted.Up to obtaining relatively large lepirudin 023 ludon by technique for gene engineering in the last few years, just make its developmental research obtain development rapidly, begun large-scale clinical practice and pharmaceutical research.Experimental result shows that the pharmacologically active of lepirudin 023 ludon and natural hirudin is consistent (Markwardt F.Thromb.Res.74:1-23,1994.) substantially.Effect obviously is better than clinically heparin of the most normal use etc., and does not have heparin-induced platelet reducing disease and become sequela such as renal failure (Doutremepuich C. with the thrombosis complex, Deharo E., Guyot, M., et al.Thrombos.Res.54:435-445,1989.).Hirudin does not have overt toxicity and antigenicity again simultaneously, in reasonable dosage, the danger that does not cause bleeding, be mainly used in the heparin-induced thrombocytopenia of treatment clinically, unstable angina pectoris (USA), acute myocardial infarction (AMI), angioplasty, disseminated inravascular coagulation (DIC); Treatment surgical operation posterior vein thrombosis promotes the healing of microsurgery wound; Behind prevention of arterial thrombosis, the especially operation on heart, prevent the thrombosis of arteria coronaria bypass; Prevent in the dynamic and static vascular behind the thrombus or form thrombosis behind the revascularization; Improve extracorporeal circulation of blood, especially medium in the hemodialysis operation.Be that hirudin or lepirudin 023 ludon all show stable chemical property, its activity is not subjected to the influence of high temperature, pH or some denaturants, only do the time spent simultaneously at high temperature and strong alkaline condition (pH 13), hirudin activity is lost (Chang J.Y.J.Bio.Chem.266:10839-10843,1991.) gradually.Hirudin is hydrophilic polypeptide, and it has good dissolubility in water.At present, the injection of lepirudin 023 ludon is got permission listing in Germany, Switzerland and the U.S., be used for the treatment of thrombocytopenia that heparin brings out, the patient's behind the Hip and Knee Replacement dvt, unstable angina and received the anticoagulation (Markwartd F.Biomed.Prog.3:19-23,1990.) that coronary artery forms the patient of art.At present, domestic also have the man unit of number to the application that State Food and Drug Administration proposes lepirudin 023 ludon crude drug and injection, wherein has 4 tame units to obtain clinical approval in 2003.Hirudin is becoming the new class medicine of control thrombus disease, has very big social benefit and economic benefit.Because hirudin is the same with other polypeptide protein class medicines, its inherent hydrophilic macromole and the characteristic that is subject to the gastrointestinal enzyme degraded, make hirudin at present mainly with the mode administration of injection, but drug administration by injection is the life-span weak point in vivo, keep effective drug duration only more than 1 hour, and be difficult to adapt to the needs of long-term anticoagulant prevention of most of chronic hypercoagulability patients and treatment.Simultaneously frequent drug administration by injection has also caused huge body and mind misery to the patient.Therefore, seek hirudin non-injection administration method, manage to prolong its action time in vivo, reduce administration number of times, improve bioavailability, become the major issue that the restriction hirudin is used, the research of its non-injection administration simultaneously also begins to be subject to people's attention, the research of currently reported lepirudin 023 ludon gastrointestinal absorption (Yang X.Y., Wang X.T., Zhang X.N.et al.J.Pharm.Exp.Thera.308 (2): 774-779,2004.) and the patent application of recombinant hirudin oral administration (Han Y.M., Lu Y.F.and Wang Z.H.Chin J Hematol20:483-484.1999).
Studies show that medicine reduces rapidly by the absorption meeting of mucosa, especially for hydrophilic compounds when molecular weight surpasses 1000.When only carrying out mucosal drug delivery (as oral, nasal cavity and rectum etc.) with simple solution as polypeptide protein class medicine, absorb very poorly, bioavailability only reaches 1% usually.Therefore injection is the main administering mode of this class medicine.Along with development of biology, increasing biochemical drug (as protein and peptide drugs) is used for the treatment of various diseases in recent years, and administering mode becomes the bottleneck of these medicinal applications of restriction.Therefore researching and developing effective non-injection administration more and more is subject to people's attention.Saturating mucosa absorption route of administration such as nasal cavity, oral cavity, oral, rectum, vagina have obtained extensive studies.
In possible polypeptide protein non-injection administration approach, the nasal mucosa administration has special advantages, they are except the characteristics that have convenient drug administration, are easy to be accepted by the patient, rich blood vessel under the nasal mucosa, medicine can directly absorb by nasal mucosa and enter the body circulation, first-pass effect when avoiding oral administration, and infiltration rate is fast, therefore is subjected to paying close attention to widely.The nasal mucosa administration also is that minority is one of polypeptide drugs non-injection administration approach of domestic and international official recognition, as the nasal cavity administrated preparation listing supply at home and abroad of polypeptide drugs such as insulin, calcitonin and vassopressin.From the situation of present research and drug development, nasal-cavity administration most possibly becomes the alternative route of administration of drug administration by injection.And the research of relevant hirudin nasal-cavity administration is not seen in any report both at home and abroad so far as yet.Therefore the development of nasal cavity taking preparation of hirudin will be opened up wide prospect more for the application of hirudin.
Yet, because nasal mucosa absorbs some intrinsic obstacles that exist for polypeptide drugs, seek out the enough bioavailability of these medicines, nasal-cavity administration still faces great challenge.These obstacles mainly are: nasal mucosa is relatively poor for the hydrophilic macromolecules permeability, makes it be difficult to see through nasal mucosa and enters blood circulation; The quick swing of cilium is unfavorable for the reservation of medicine at nasal cavity to drug induced scavenging action in the nasal mucosa in addition.Using absorption enhancer at present is to improve the main method that the polypeptide drug nasal mucosa absorbs, yet the most ciliation toxic action of absorption enhancer easily becomes infringement to nasal mucosa.Therefore seeking the absorption enhancer of high-efficiency low-toxicity, or increase the time of staying of hirudin in nasal cavity, is the key of nasal cavity administrated preparation development.
The objective of the invention is in order to overcome hirudin mucosa malabsorption, improve bioavailability, reduce nasal mucosa toxicity, a kind of effective nasal mucosa administration novel formulation that is used for the treatment of the cardiovascular and cerebrovascular disease that causes with pre-preventing thrombosis and preparation method thereof is provided, and the application of said preparation.
Summary of the invention
The present invention adopts absorption enhancer or has the chitosan of bio-adhesive characteristic (also being absorption enhancer simultaneously) and share with absorption enhancer, can increase permeability and/or the time of staying of medicine at the nasal mucosa position, improve bioavailability of medicament, can guarantee nasal mucosa is not produced tangible zest and toxic action simultaneously.
The objective of the invention is to be achieved through the following technical solutions:
Pharmaceutical formulation of the present invention consists of:
Hirudin 50～500mg
Absorption enhancer 5～100mg
Antiseptic 0.1～4mg
PH to 4.5～6.0 are transferred in the pH regulator agent in right amount
Water or normal saline add to 1ml
With above-mentioned prescription, or further add the conventional adjuvant of other conventional ratios, be prepared into nasal cavity taking preparation of hirudin, can be drop, gel, spray or ointment.
The antiseptic that above-mentioned preparation adopted is benzalkonium bromide or sodium benzoate, or methyl hydroxybenzoate and propyl hydroxybenzoate or ethyl hydroxybenzoate and propyl hydroxybenzoate are share, and its concentration in preparation is 0.01～0.4% (w/v).
Absorption enhancer in the above-mentioned preparation is selected from one or more of following kind of apoplexy due to endogenous wind, and its kind and the bulking value percentage composition in preparation are respectively: chitosan (CS) is 0.5～1.5%; Tween 80 (Tween80) is 2～7% (w/v); HP-(2～10% (w/v) of HP-β-CD); Monoammonium glycyrrhizinate 0.5～2% (GMA, w/v).Direct water-soluble or normal saline in preparation process, or be dissolved in earlier in the minor amounts of propylene glycol in the water-soluble again or normal saline.
Above-mentioned absorption enhancer except that chitosan can share with the following column weight amount of the chitosan of 0.25～1.0% percent weight in volume consumption percent by volume: tween 80 (Tween80) is 2～7% (w/v); HP-(2～10% (w/v) of HP-β-CD); Monoammonium glycyrrhizinate 0.5～2% (GMA, w/v).
The hirudin that above-mentioned preparation adopted is natural hirudin or the lepirudin 023 ludon by genetic engineering preparation.
The preparation technology of preparation of the present invention is: the antiseptic of formula ratio is added in suitable quantity of water or the normal saline, after stirring (or heating) makes it dissolving, add successively after absorption enhancer (in case of necessity earlier dissolve with propylene glycol), hirudin stir and make it to dissolve fully, add remainder water or normal saline, transfer pH to 4.5～6.0 with acetic acid, promptly.This method can be used for the preparation of nasal drop or nasal spray; Can be made into ointment or gel if add the conventional adjuvant of conventional ratio again.
Nasal cavity taking preparation of hirudin of the present invention is used to prevent and/or treat the application of various thrombotic disease after by nasal-cavity administration.
The prescription system of various proportionings of the present invention is through preferably drawing.Each prescription bioavailability test in the body, the test of pesticide effectiveness, mucosa irritation and cilium toxicity test behind the animal nasal-cavity administration prove that selected prescription and matched group more all can obviously improve hirudin bioavailability (P＜0.05) in the rat body; Can obviously prolong the clotting time (P＜0.05) of normal rat; The clotting time of model (DIC) rabbit of disseminated inravascular coagulation is shortened near normal value, relatively have significant difference (P＜0.05) with model group; And zest and cilium toxicity and blank comparison there was no significant difference to mucosa show that zest and cilium toxicity are less.Following animal experiment is in order to illustrate above-mentioned effectiveness and safety:
Absorption test in the rat body
Hirudin provided by the invention respectively fill a prescription behind the per nasal mucosal drug delivery in the rat body bioavailability test following (hirudin that adopts in the test is a lepirudin 023 ludon-2, rHV-2):
Variable concentrations chitosan (0.5%, 1%, 1.5%; W/v, pH 5.0), tween 80 (2%, 5%, 7%; W/v), HP-(2%, 5%, 10%; W/v), monoammonium glycyrrhizinate (GMA, 0.5%, 1%, 2%; The prescription of forming with rHV-2 such as w/v), can make area (AUC) and relative bioavailability (Fr under the intravital blood drug level-time graph of rat behind the rHV-2 nose administration, compare with subcutaneous injection) relatively obtain obvious raising (P＜0.05 sees Table 1) with the normal saline matched group.
The various rHV2 of table 1 fill a prescription to AUC in the rat body behind the rHV-2 nose administration with relative
The influence of bioavailability
| CS concentration % | RHV2 dosage (mgkg -1) | AUC 0-6(μg·min·ml -1) ±SD | Fr％ |
| CS(0.5％)+rHV2 CS(1.0％)+rHV2 CS(1.5％)+rHV2 Tween80(1％)+rHV2 Tween80(5％)+rHV2 Tween80(7％)+rHV2 GMA(0.5％)+rHV2 GMA(1.0％)+rHV2 GMA(2.0％)+rHV2 HP-β-CD(2.0％)+rHV2 | 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 | 16.14±6.40 21.34±9.07 24.50±9.13 17.78±6.29 57.46±26.03 68.79±20.84 9.59±4.06 15.87±5.83 19.59±6.17 10.55±3.88 | 7.66 ** 10.14 ** 11.63 ** 8.44 ** 27.29 ** 32.66 * 4.55 * 7.53 ** 9.30 ** 5.01 * |
| HP-β-CD (5.0%)+rHV2 HP β-CD (10.0%)+rHV2 rHV2 (being dissolved in 0.9%NaCl) rHV2 (SC) | 6.0 6.0 6.0 0.5 | 22.90±10.01 27.78±5.83 4.50±1.75 35.10±9.74 | 10.87 ** 13.19 ** 2.14 100 |
Annotate: AUC and relative bioavailability data are calculated through trapezoidal method by the in vivo test result, are meansigma methods ± standard deviation, (n=5～6)
Fr% is and subcutaneous injection relative bioavailability relatively
P＜0.05 relatively has significant difference with the normal saline group
*P＜0.01 relatively has utmost point significant difference with the normal saline group
SC: subcutaneous injection
RHV2: hirudin-2
CS: chitosan
The test solvent for use is normal saline
The cilium toxicity test
Employing is in body toad palate modelling: observe each prescription and rHV-2 to the influence of persistent movement time of toad palate cilium, calculate the cilium persistent movement percentage rate of administration group with respect to the normal saline group, and with sodium lauryl sulphate as positive controls.RHV-2 reaches the influence that is respectively tried to fill a prescription to cilium persistent movement situation and sees Table 2 as a result.
Table 2 hirudin, absorption enhancer and antiseptic are to effect on ciliary movement (n=5)
| Prescription | The relative persistent movement percentage rate ± SD/ of cilium (%) |
| rHV2(5％) rHV2(50％) CS(0.5％) CS(1.0％) CS(1.5％) Tween80(1％) Tween80(5％) Tween80(7％) GMA(0.5％) GMA(1.0％) GMA(2.0％) HP-β-CD(2.0％) HP-β-CD(5.0％) | 99.23±11.62 98.77±10.65 97.65±9.34 95.25±5.40 90.27±8.60 87.33±9.85 85.77±6.73 80.71±11.25 98.91±10.15 95.38±8.22 93.45±8.44 95.52±5.87 94.10±7.65 |
| HP-β-CD (10.0%) methyl hydroxybenzoate ethyl hydroxy benzoate Nipasol benzalkonium bromide Sodium Benzoate 0.9%NaCl 1%SDS | 93.12±13.22 98.18±7.24 95.33±6.95 95.55±10.30 96.74±9.87 96.45±12.42 100 19.45±15.78 |
Annotate: data are meansigma methods ± standard deviation (n=5)
RHV2: lepirudin 023 ludon-2
CS: chitosan
HP-β-CD: HP-
GMA: monoammonium glycyrrhizinate
SDS: sodium lauryl sulphate
The test solvent for use is normal saline
Table 2 result shows the relative persistent movement percentage rate of the cilium of each test group all more than 90%, handles by statistics, with PBS group relatively there are no significant difference (P＞0.05).The cilium toxic action that shows each prescription is less.
Irritation test
The 1 hirudin zest of single-dose of respectively filling a prescription to the rabbit eyes
Adopt tame lagophthalmos mucosa irritation test method(s): the administration of rabbit left eye, the right eye contrast checks that respectively at 1h, 2h, 3h, 4h, 24h, 48h, 72h after the administration eye mask has or not cornea hyperemia, edema, ulcer and muddiness etc.Right and left eyes is observed no significant difference after each prescription group of hirudin (with bioavailability test in the rat body) administration as a result, and illustrating does not have obvious irritation to the eye mucosa.
The 2 hirudins zest of multiple dosing of respectively filling a prescription to the rabbit eyes
Adopt tame lagophthalmos mucosa irritation test method(s): the administration of rabbit left eye, the another eyes do not process, in contrast.Administration every day 3 times, 10d observes the lagophthalmos response situation before administration every day continuously, observes 7d after the drug withdrawal more continuously.Right and left eyes is observed no significant difference after hirudin and each prescription group (with bioavailability test in the rat body) administration as a result, and illustrating does not have obvious irritation to the eye mucosa.
The test of pesticide effectiveness
1 measures hirudin respectively fills a prescription behind the nose administration to the influence of normal rat partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT):
With the rHV-2 solution of different formulations preparation, per nasal gives rat 25 μ l (6.0mg.kg
-1), get blood behind the 1h, measure the variation of partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) respectively.Each group of result all obviously prolongs (P＜0.05) than the clotting time of hirudin saline control group.(seeing Table 3).
The various prescriptions of table 3 hirudin to the hirudin nose administration after to the influence (n=5～6) of normal rat clotting time
| Formulations | APTT(sec) | PT(sec) | TT(sec) |
| CS, (0.5%)+rHV2 CS, (1.0%)+rHV2 CS, (1.5%)+rHV2 Tween80, (1%)+rHV2 Tween80, (5%)+rHV2 Tween80, (7%)+rHV2 GMA, (0.5%)+rHV2 GMA, (1.0%)+rHV2 GMA, (2.0%)+rHV2 HP-β-CD, (2.0%)+rHV2 HP-β-CD, (5.0%)+rHV2 HP-β-CD, (10.0%)+rHV2 rHV2, (being dissolved in 0.9%NaCl) | 51.4±20.6 * 46.9±15.8 * 52.5±22.3 * 70.4±24.5 * 78.2±32.6 * 83.3±28.6 * 60.6±30.7 * 68.2±33.7 * 75.4±29.9 * 43.9±15.2 * 56.6±20.8 * 69.1±35.4 25.8±9.3 | 31.2±10.7 * 34.4±11.5 * 36.8±8.7 * 43.4±15.5 * 49.7±12.2 * 52.0±14.8 * 33.7±9.9 * 38.5±11.5 * 41.6±8.3 * 33.3±8.5 * 35.0±11.5 * 42.6±10.3 * 17.2±6.10 | 38.1±12.7 * 36.3±10.5 * 39.4±9.7 * 49.4±11.5 * 55.7±18.2 * 62.6±24.6 * 50.6±19.4 * 56.8±18.3 * 63.1±28.2 * 38.3±12.5 * 45.5±19.5 * 48.4±13.4 * 22.4±6.3 |
Annotate:
*P＜0.05 relatively has significant difference with the normal saline group
RHV2: lepirudin 023 ludon-2
CS: chitosan
HP-β-CD: HP-
GMA: monoammonium glycyrrhizinate
The rHV2 dosage is 6mg/kg
The test solvent for use is normal saline.
2 measure hirudins respectively fills a prescription behind the nose administration to the influence of disseminated inravascular coagulation model (DIC) rabbit clotting time
Adopt bacterial endotoxin (LPS) interval 24h intravenous injection (2.5 μ g/kg, 5 μ g/kg) to cause rabbit DIC model, nasal cavity gives lepirudin 023 ludon nasal cavity administrated preparation (2mg.kg
-1), the 3h vein is got blood after the administration, measures the variation of APTT value.(the results are shown in Table 4).
Behind the various prescription nose administrations of table 4 hirudin to the influence (n=5) of DIC rabbit clotting time
| Formulations | APTT(sec) |
| CS, (0.5%)+rHV2 CS, (1.0%)+rHV2 CS, (1.5%)+rHV2 Tween80, (1%)+rHV2 Tween80, (5%)+rHV2 Tween80, (7%)+rHV2 GMA, (0.5%)+rHV2 GMA, (1.0%)+rHV2 GMA, (2.0%)+rHV2 HP-β-CD, (2.0%)+rHV2 HP-β-CD, (5.0%)+rHV2 HP-β-CD, (10.0%)+rHV2 rHV2, (being dissolved in 0.9%NaCl) model control group Normal group | 24.5±8.9 ▲ 27.9±10.9 ▲ 26.1±9.9 ▲ 26.1±11.2 ▲ 25.7±10.5 ▲ 25.6±9.5 ▲ 25.5±10.9 ▲ 25.2±10.5 ▲ 24.8±10.3 ▲ 25.8±10.2 ▲ 25.5±8.8 ▲ 24.9±10.9 ▲ 39.7±9.7 * 40.5±14.5 * 22.3±9.3 |
Annotate:
*P＜0.05 relatively has significant difference with normal control (0.9%NaCl) group
▲P＜0.05 relatively has significant difference with model control group
RHV2: lepirudin 023 ludon-2
The rHV2 dosage is 2mg/kg
The test solvent for use is normal saline
CS: chitosan
GMA: monoammonium glycyrrhizinate
HP-β-CD: HP-
The result shows: each test group obviously shortens than the clotting time of model group, near normal value.Illustrate that each test group has anticoagulation and anti-thrombosis function preferably.
Nasal cavity taking preparation of hirudin provided by the invention is mainly used in prevention and treats the application of various thrombotic disease.
Dosage: this product 1ml hirudin 50～500mg, every day 1～3 time, one-sided or bilateral nasal mucosa medicine administration, use amount is according to the difference of administration purpose and different.
Packing: this product is packaged as the special-purpose bottle of nasal drop, nasal spray or ointment.
The specific embodiment
Embodiment 1
Hirudin 200mg
Chitosan 5mg
Benzalkonium bromide 0.35mg
Acetic acid is transferred pH4.5-5.5 in right amount
Water adds to 1ml
Technology: the formula ratio chitosan is added in suitable quantity of water or the normal saline, drip acetic acid and make dissolving fully, add successively after benzalkonium bromide, hirudin stir and make it to dissolve fully, add the remainder normal saline, transfer pH to setting, promptly with acetic acid or NaOH.
Can make drop or spray with this technology; Add an amount of conventional adjuvant such as polyvinyl alcohol (PVA) or carbopol again, mix can be made into gel or ointment with proper proportion mutually.
Embodiment 2
Hirudin 500mg
Chitosan 10mg
Sodium benzoate 1.5mg
Acetic acid is transferred pH4.5～5.5 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 1.
Embodiment 3
Hirudin 300mg
Chitosan 5mg
Tween 80 20mg
Benzalkonium bromide 0.35mg
Acetic acid is transferred pH5.0 in right amount
Water adds to 1ml
Technology: the formula ratio chitosan is added in suitable quantity of water or the normal saline, drip acetic acid and make dissolving fully, add successively after benzalkonium bromide, tween 80, hirudin stir and make it to dissolve fully, add the remainder normal saline, transfer pH to setting, promptly with acetic acid or NaOH.
Can make drop or spray with this technology; Add an amount of conventional adjuvant such as polyvinyl alcohol (PVA) or carbopol again, mix can be made into gel or ointment with proper proportion mutually.
Embodiment 4
Hirudin 200mg
Chitosan 10mg
Tween 80 50mg
Sodium benzoate 2mg
Acetic acid is transferred pH4.5～5.5 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 3.
Embodiment 5
Hirudin 50mg
Chitosan 25mg
Tween 80 50mg
Sodium benzoate 2mg
Acetic acid is transferred pH4.5～5.5 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 3.
Embodiment 6
Hirudin 100mg
Chitosan 5mg
Tween 80 70mg
Sodium benzoate 2mg
Acetic acid is transferred pH4.5～5.5 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 3.
Embodiment 7
Hirudin 300mg
Monoammonium glycyrrhizinate 10mg
Benzalkonium bromide 0.3mg
Acetic acid is transferred pH5.0～6.0 in right amount
Normal saline adds to 1ml
Technology: the recipe quantity benzalkonium bromide is added in an amount of normal saline, make fully dissolving, add successively after monoammonium glycyrrhizinate, hirudin stir and make it to dissolve fully, add the remainder normal saline, transfer pH to setting, promptly with acetic acid.
Can make drop or spray with this technology; Add an amount of conventional adjuvant again as poly-rare alcohol (PVA) or carbopol, mix can be made into gel or ointment with proper proportion mutually.
Embodiment 8
Hirudin 300mg
Monoammonium glycyrrhizinate 20mg
Benzalkonium bromide 0.3mg
Acetic acid is transferred pH5.0～6.0 in right amount
Normal saline adds to 1ml
Preparation technology is identical with embodiment 7.
Embodiment 9
Hirudin 300mg
Chitosan 5mg
Monoammonium glycyrrhizinate 10mg
Benzalkonium bromide 0.3mg
Acetic acid is transferred pH4.5～5.5 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 3.
Embodiment 10
Hirudin 200mg
Chitosan 10mg
Monoammonium glycyrrhizinate 5mg
Sodium benzoate 2mg
Acetic acid is transferred pH4.5～5.5 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 3.
Embodiment 11
Hirudin 200mg
Chitosan 5mg
HP-20mg
Benzalkonium bromide 0.3mg
Acetic acid is transferred pH4.5～5.5 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 3.
Embodiment 12
Hirudin 200mg
Chitosan 10mg
HP-70mg
Benzalkonium bromide 0.3mg
Acetic acid is transferred pH4～6 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 3.
Embodiment 13
Hirudin 300mg
HP-20mg
Benzalkonium bromide 0.3mg
Acetic acid is transferred pH5.0～6.0 in right amount
Normal saline adds to 1ml
Preparation technology is identical with embodiment 7.
Embodiment 14
Hirudin 100mg
HP-70mg
Benzalkonium bromide 0.3mg
Acetic acid is transferred pH5.0～6.0 in right amount
Water or normal saline add to 1ml
Preparation technology is identical with embodiment 7.
Embodiment 15
Hirudin 500mg
Chitosan 5mg
Tween 80 50mg
Methyl hydroxybenzoate 1.3mg
Propyl hydroxybenzoate 0.2mg
Acetic acid is transferred pH4.5～5.5 in right amount
Water adds to 1ml
Technology: the recipe quantity chitosan is added in an amount of normal saline, drip acetic acid, stir to make fully and dissolve, other gets methyl hydroxybenzoate and the ethyl hydroxybenzoate heating makes dissolving fully, put cold after, adding chitosan solution, tween 80, hirudin successively stirs and makes it to dissolve fully, add the remainder normal saline, transfer pH to setting, promptly with acetic acid or NaOH.
Can make drop or spray with this technology; Add an amount of conventional adjuvant such as polyvinyl alcohol (PVA) or carbopol again, mix can be made into gel or ointment with proper proportion mutually.
Embodiment 16
Hirudin 200mg
Tween 80 50mg
Ethyl hydroxybenzoate 1.5mg
Propyl hydroxybenzoate 1.5mg
Acetic acid is transferred pH5.0～6.0 in right amount
Water adds to 1ml
Technology: recipe quantity ethyl hydroxybenzoate and propyl hydroxybenzoate are added in an amount of normal saline, and heating makes fully dissolving, put cold after, adding tween 80, hirudin successively stirs and makes it to dissolve fully, add the remainder normal saline, transfer pH to setting, promptly with acetic acid or NaOH.
Can make drop or spray with this technology; Add an amount of conventional adjuvant such as polyvinyl alcohol (PVA) or carbopol again, mix can be made into gel or ointment with proper proportion mutually.
Embodiment 17
Hirudin 300mg
HP-50mg
Methyl hydroxybenzoate 1.3mg
Propyl hydroxybenzoate 0.2mg
Acetic acid is transferred pH5.0～6.0 in right amount
Water adds to 1ml
Preparation technology is identical with embodiment 15.
Embodiment 18
Hirudin 300mg
Monoammonium glycyrrhizinate 10mg
Methyl hydroxybenzoate 1.3mg
Propyl hydroxybenzoate 0.2mg
Acetic acid is transferred pH5.0～6.0 in right amount
Normal saline adds to 1ml
Preparation technology is identical with embodiment 16.
Claims (8)
1 one kinds of nasal cavity taking preparation of hirudin is characterized in that the component comprising following percent weight in volume:
Hirudin 5～50% (w/v)
Absorption enhancer 0.5～10% (w/v)
Antiseptic 0.01～0.4% (w/v)
The pH regulator agent is an amount of, transfers to pH4.5～6.0
Water or normal saline add to ormal weight
Antiseptic is benzalkonium bromide or sodium benzoate, or methyl hydroxybenzoate and propyl hydroxybenzoate or ethyl hydroxybenzoate and propyl hydroxybenzoate are share.
2 preparations according to claim 1 is characterized in that absorption enhancer is one or more of following kind apoplexy due to endogenous wind, and its kind and percent weight in volume content are respectively:
Chitosan 0.25～1.5% (w/v)
HP-2～10% (w/v)
Tween 80 2～7% (w/v)
Monoammonium glycyrrhizinate 0.5～2% (w/v)
3 preparations according to claim 2, it is characterized in that except that chitosan absorption enhancer by claim 2 described separately percent weight in volume and the chitosan of 0.25～1.0% percent weight in volume share.
4 according to the described preparation of claim 1,2 or 3, it is characterized in that hirudin is natural hirudin or the lepirudin 023 ludon by gene recombination technology preparation.
5 according to claim 1,2 or 3 described preparations, it is characterized in that preparing by the following method: the antiseptic of recipe quantity is added in suitable quantity of water or the normal saline, after stirring (or heating) makes it dissolving, add successively after absorption enhancer (in case of necessity earlier dissolve with propylene glycol), hirudin stir and make it to dissolve fully, add remainder water or normal saline, transfer pH to setting, promptly with acetic acid.
6. according to the described preparation of claim 5, it is characterized in that making nasal drop or nasal spray.
7. according to the described preparation of claim 5, it is characterized in that the conventional adjuvant that adds conventional ratio again makes ointment or gel.
8. prevent and/or treat the purposes of the medicine of various thrombotic disease in preparation according to the described preparation of claim 1,2 or 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510073407 CN1872337A (en) | 2005-05-30 | 2005-05-30 | Nasal cavity taking preparation of hirudin, and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510073407 CN1872337A (en) | 2005-05-30 | 2005-05-30 | Nasal cavity taking preparation of hirudin, and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1872337A true CN1872337A (en) | 2006-12-06 |
Family
ID=37483045
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510073407 Pending CN1872337A (en) | 2005-05-30 | 2005-05-30 | Nasal cavity taking preparation of hirudin, and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1872337A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810561A (en) * | 2009-02-20 | 2010-08-25 | 北京大学 | Hirudin polyion micelle composition |
| CN108066281A (en) * | 2017-12-30 | 2018-05-25 | 陕西慧康生物科技有限责任公司 | Treat the Liraglutide nasal drop of type-2 diabetes mellitus |
-
2005
- 2005-05-30 CN CN 200510073407 patent/CN1872337A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810561A (en) * | 2009-02-20 | 2010-08-25 | 北京大学 | Hirudin polyion micelle composition |
| CN101810561B (en) * | 2009-02-20 | 2013-06-05 | 北京大学 | Hirudin polyion micelle composition |
| CN108066281A (en) * | 2017-12-30 | 2018-05-25 | 陕西慧康生物科技有限责任公司 | Treat the Liraglutide nasal drop of type-2 diabetes mellitus |
| CN108066281B (en) * | 2017-12-30 | 2020-07-21 | 陕西慧康生物科技有限责任公司 | Liraglutide nasal drops for treating type II diabetes |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1304049C (en) | Pharmaceutical composition comprising factor VIIa and factor XIII | |
| CN1241569C (en) | Novel combination of non sedative anti histamines containing substances which influence the action of leukotriene, for treating rhinitis/conjuncitivitis | |
| CN1108655A (en) | 1,3-oxathiolane nucleoside analogues | |
| CN1433307A (en) | Prostaglandin compounds for treating congestive heart failure | |
| CN1126548C (en) | Use of zinc hyaluronate against peptic ulcer | |
| CN100350908C (en) | Novel anti-allergic anti-inflammatory composite | |
| CN100345589C (en) | Essential element nutritive preparation for intestine | |
| CN1723021A (en) | Stable solid medicinal composition for oral administration. | |
| CN1625405A (en) | Combinations comprising cox-2 inhibitors and aspirin | |
| CN1931167A (en) | Double layer osmotic pump controlled release felodipine medicine composition | |
| CN1872337A (en) | Nasal cavity taking preparation of hirudin, and application | |
| CN1872278A (en) | A composition of medication | |
| CN1438886A (en) | Ophthalmic solution | |
| CN101036642A (en) | Ginkgolide B nanometric liposomes medicine and the preparing method thereof | |
| CN1729998A (en) | Cancer treating | |
| CN1552438A (en) | Medicine for decreasing vagina acidity and treating vaginitis, use thereof | |
| CN1861064A (en) | Medicine composition contg. sodium azulene sulfonate and L-glutamine water-soluble precursor | |
| CN1896092A (en) | Lysine aescin saponin, its preparation and use | |
| CN1350463A (en) | A Pharmaceutical formulation containing an inhibitor of carboxypeptidase U and a thrombin inhibitor | |
| CN1876004A (en) | A medicament for treating cerebrovascular disease | |
| CN1895218A (en) | Pyrrolechrisxi and its sodium-salt eye-gel preparation and its making method | |
| CN1927206A (en) | Lornoxicam composition for injection and preparation process thereof | |
| CN101031297A (en) | Pharmaceutical composition for xerophthalmia and xerostomia treatment | |
| CN1084061A (en) | Agent for treating cataract and preparation method thereof | |
| CN1631358A (en) | Compound pseudoephedrine hydrochloric acid containing powder for treating cold, its prescription and preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20061206 |